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| United States Patent |
5,182,273
|
|
Duflos
, et al.
|
January 26, 1993
|
Spirocyclic N, O derivatives of cyclotriphosphazenes and their use in
therapy
Abstract
The present invention relates to compounds of the Formula I:
##STR1##
wherein R is hydrogen, alkyl, cycloalkyl, phenyl, or alkylphenyl, and n is
2 through 4, the production thereof, pharmaceutical compositions thereof,
and their use in antineoplastic therapy.
| Inventors:
|
Duflos; Alain (Castres, FR);
Patoiseau; Jean-Francois (Castres, FR);
Bigg; Dennis (Castres, FR);
Kiss; Robert (Castres, FR)
|
| Assignee:
|
Pierre Fabre Medicament (Boulogne, FR)
|
| Appl. No.:
|
780480 |
| Filed:
|
October 22, 1991 |
Foreign Application Priority Data
| Current U.S. Class: |
514/83; 548/957 |
| Intern'l Class: |
A61K 031/395; C07D 403/14 |
| Field of Search: |
548/957
514/83
|
References Cited
U.S. Patent Documents
| 4595682 | Jun., 1986 | Labarre et al. | 514/83.
|
Other References
S. S. Krishnamurthy et al., J. C. S. Dalton 1980, pp. 840-844.
V. Chandrasekhar et al., Inorg. Nucl. Chem. Letters, 1981, vol. 17, No.
5-6, pp. 181-185.
|
Primary Examiner: Brust; Joseph Paul
Assistant Examiner: Haley; Jacqueline
Attorney, Agent or Firm: Hueschen; Gordon W.
Claims
We claim:
1. A compound selected from those having the Formula I
##STR8##
in which: R represents hydrogen, linear, branched or cyclic C.sub.1-6
alkyl, phenyl, or alkylphenyl phenyl (CH.sub.2).sub.m --, m being 1 to 4
inclusive, and
n=2, 3, or 4.
2. A compound according to claim 1, wherein R is selected from the group
consisting of hydrogen, methyl, cyclohexyl, benzyl, and phenethyl.
3. A compound of claim 1 which is
4-methyl-7,7,9,9-tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,8,10-tetr
aaza-5.lambda..sup.5 -7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene.
4. A compound of claim 1 which is
11-phenylmethyl-2,2,4,4-tetra-1-aziridinyl-2,2,4,4,-tetrahydro-7-oxa-1,3,5
,11-tetraaza-2,4,6.lambda..sup.5
-triphosphaspiro-[5,5]-undeca-1,3,5-triene.
5. A compound of claim 1 which is
2,2,4,4-tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,5,12-tetraaza-2,4,
6.lambda..sup.5 -triphosphaspiro-[5,6]-dodeca-1,3,5-triene.
6. A compound of claim 1 which is
7,7,9,9-tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,8,10-tetraaza-5.la
mbda..sup.5,7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene.
7. A compound of claim 1 which is
2,2,4,4-tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,5,11-tetraaza-2,4,
6.lambda..sup.5 -triphosphaspiro-[5,5]-undeca-1,3,5-triene.
8. A compound of claim 1 which is
11-cyclohexyl-2,2,4,4-tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,5,11
-tetraaza-2,4,6.lambda..sup.5 -triphosphaspiro-[5,5]-undeca-1,3,5-triene.
9. A compound of claim 1 which is
4-phenylmethyl-7,7,9,9-tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,8,1
0-tetraaza-5.lambda..sup.5,7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene.
10. A compound of claim 1 which is
4-(2-phenylethyl)-7,7,9,9-tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,
8,10-tetraaza-5.lambda..sup.5,7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene.
11. A compound of claim 1 which is
11-(2-phenylethyl)-2,2,4,4-tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3
,5,11-tetraaza-2,4,6.lambda..sup.5
-triphosphaspiro-[5,5]-undeca-1,3,5-triene.
12. An antineoplastic pharmaceutical composition containing as active
principle an effective antineoplastic amount of a compound of claim 1
together with a pharmaceutically-acceptable carrier or diluent.
13. The pharmaceutical composition of claim 12, wherein the compound is
present in an amount of about 10 mg to about 200 mg per unit dose.
14. A method for the treatment of a neoplastic disease or condition, which
is responsive to treatment with a compound of claim 1 and susceptible
thereto, in a living being comprising the step of administering to the
living being an effective antineoplastic amount of a compound of claim 1.
15. The method of claim 14 wherein the compound is administered in the form
of a pharmaceutical composition thereof in which it is present together
with a pharmaceutically-acceptable carrier or diluent.
Description
FIELD OF THE INVENTION
The present invention relates to new chemical compounds, pharmaceutical
compositions thereof, their method of preparation, and their use as
antineoplastic medicaments.
The new chemical compounds have the general Formula I
##STR2##
in which:
R represents hydrogen, a linear, branched, or cyclic C.sub.1-6 alkyl
radical, a phenyl radical, or an alkylphenyl radical phenyl
(CH.sub.2).sub.m --, m being 1 to 4 inclusive and, by way of illustration
but not of limitation, H, Me, cyclohexyl, phenyl, benzyl, or phenethyl,
whereas n=2, 3, or 4.
The present invention also relates to the use of a compound of general
Formula I as an antineoplastic medicament and to pharmaceutical
compositions containing such active ingredient or principle together with
a pharmaceutically-acceptable diluent or carrier.
The pharmaceutical compositions of the present invention embody a compound
of general Formula I, possibly together with one or more other active
principles, in addition to the same pharmaceutically-acceptable diluent or
carrier.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide new chemical compounds,
a method for the preparation thereof, pharmaceutical compositions
embodying the same, and a method for their use in antineoplastic therapy
against neoplastic ailments or conditions susceptible thereto.
Still other objects of the invention will become apparent hereinafter and
still further objects of the invention will be apparent to one skilled in
the art.
SUMMARY OF THE INVENTION
The invention, then, comprises the following aspects, singly or in
combination:
New compounds selected from those having general Formula I as set forth
herein; especially such compounds wherein R is selected from hydrogen,
methyl, cyclohexyl, benzyl, and phenethyl; especially those compounds set
forth herein as Compounds 1 through 9; pharmaceutical compositions of such
compounds together with a pharmaceutically-acceptable diluent or carrier;
and a method of employing a compound of the invention or a pharmaceutical
composition thereof for the antineoplastic treatment or alleviation of a
susceptible neoplastic ailment or condition by administration of the same
to a patient, whether animal or human, in need thereof.
PREPARATION
The methods of synthesis of the compounds of general Formula I also form a
part of the present invention.
Synthesis of the Compounds of General Formula I
The compounds of the present invention are obtained from
hexachlorocyclotriphosphazene II via a tetrachlorinated intermediary III,
in which the symbols R and n have the same meaning as given for I.
##STR3##
Compounds III can be obtained by the method described in the literature, in
particular by:
S. S. KRISHNAMURTHY et al., J. C. S. Dalton 1980, pp. 840-844.
V. CHANDRASEKHAR et al., Inorg. Nucl. Chem. Letters, 1981, Vol, 17, No.
5-6, pp. 181-185.
These methods comprise the treatment of hexachlorocyclotriphosphazene
(N.sub.3 P.sub.3 Cl.sub.6) with a hydroxyamine IV, preferably in the
presence of a hydrochloric acid acceptor such as a tertiary amine, e.g.,
triethylamine, in a solvent such as tetrahydrofuran (THF).
R--NH--(CH.sub.2).sub.n --OH IV
It is also possible to produce the intermediate III by carrying out the
reaction in a two-phase medium such as THF/soda.
The aziridination of the intermediate III, to obtain a compound of the
present invention, is effected using aziridine in a solvent such as THF in
the presence of a tertiary amine hydrochloric acid acceptor such as, for
instance, triethylamine.
The following examples illustrate the invention without limiting its scope.
EXAMPLE 1
Compound 1
4-methyl-7,7,9,9-tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,8,10-tetra
aza-5.lambda..sup.5 -7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene
##STR4##
a) Eight (8) g (106 mmols) of N-methyl-2-aminoethanol, 300 ml of THF and
266 ml of 1N aqueous caustic soda are introduced into a one-liter reactor.
With vigorous agitation at 25.degree. C., the N.sub.3 P.sub.3 Cl.sub.6 is
introduced all at once, the temperature being maintained below 35.degree.
C. After one hour at 30.degree. C., the aqueous phase is saturated with
sodium chloride and then, after decantation, extracted with ethyl ether.
The two organic phases, combined, are evaporated to dryness. The residue,
taken up in a minimum amount of methylene chloride, is percolated through
a silica column (20 g) and eluted with a 1:1 mixture of methylene chloride
and ethyl acetate.
After evaporation, the residue is agitated in hexane for 30 minutes.
After filtering and drying at 40.degree. C. under vacuum, 26 g of
tetrachlorinated intermediate are obtained.
Yield: 70%-MP=137.degree. C.
b) The compound obtained above (17.5 g, 50 mmols) is placed in solution in
250 ml of THF containing triethylamine (30 g-300 mmols). Aziridine (12.9
g, 300 mmols), diluted in THF (50 ml) is added at -10.degree. C. over the
course of 15 minutes.
After agitation for 1 hour at 0.degree. C. and 48 hours at 25.degree. C.,
the hydrochloride crystals are filtered off and the THF is partially
evaporated. The solution obtained is percolated through a silica column
(50 g) and eluted with THF (150 ml).
After evaporation to dryness and recrystallization of the residue from THF,
the compound 1 (10.5 g) is obtained.
Yield: 56%; MP=170.degree. C.
EXAMPLE 2
Compound 6
11-Phenylmethyl-2,2,4,4-tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,5,1
1-tetraaza-2,4,6.lambda..sup.5 -triphosphaspiro-[5,5]-undeca-1,3,5-triene.
##STR5##
a) Ten (10) g (0.0287 mol) of N.sub.3 P.sub.3 Cl.sub.6 and 165 ml of
tetrahydrofuran (THF) are introduced into a double-jacketed 250-ml reactor
maintained at 0.degree. C. After dissolution, 8 ml (0.0575 mol) of
triethylamine is added and thereafter a solution comprising 5.2 g (0.0316
mol) of 3-benzylaminopropanol in 35 ml of THF is added dropwise over a
period of thirty minutes. The reaction mixture is agitated for an
additional hour at 0.degree. C. plus an additional fifteen hours at
20.degree. C.
The insoluble material is filtered off and the THF evaporated. The residue
is dissolved with a miminum of methylene chloride and the solution thus
obtained is percolated through a silica (20 g) column. Upon elution of the
column with a mixture of methylene chloride and ethyl acetate 1/1, the
fractions containing the product are combined and evaporated and the
residue is agitated with a mixture comprising 40 ml of hexane and 5 ml of
isopropylether. The crystals are collected by filtration, dried, and
rinsed with hexane. After drying at approximately 40.degree. C., one
obtains 7 g of
11-phenylmethyl-2,2,4,4-tetrachloro-2,2,4,4-tetrahydro-7-oxa-1,3,5,11-tetr
aaza-2,4,6.lambda..sup.5 -triphosphaspiro-[5,5]-undeca-1,3,5-triene.
Yield 55%; MP 112.degree. C.
b) A solution of the compound from the preceding step (5 g, 0.0113 mol) in
65 ml of THF is introduced into a 250-ml double-jacketed reactor.
Thereafter 10.9 ml (0.078 mol) of triethylamine is introduced at a
temperature of approximately -10.degree. C. A solution comprising 4 ml
(0.078 mol) of aziridine and 15 ml of THF is then added dropwise over a
period of fifteen minutes. The reaction mixture is agitated at -10.degree.
C. for a period of one hour and then at a temperature of 20.degree. C. for
a period of 48 hours. The insoluble product is removed by filtration and
the THF evaporated to half volume. The remaining solution is
chromatographed by passage through a column of silica (50 g) using THF as
eluant. Evaporation of the fractions containing the product and
recrystallization of the residue from 120 ml of a mixture comprising 50%
diisopropyl ether and ethyl acetate affords a crystalline product which is
rinsed with diisopropyl ether. After drying at a temperature of about
40.degree. C., 2.65 g of Compound 6 are obtained.
Yield 50%; MP=133.degree. C.
EXAMPLE 3
Compound 9
2,2,4,4-Tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,5,12-tetraaza-2,4,6
.lambda..sup.5 -triphosphaspiro-[5,6]-dodeca-1,3,5-triene.
##STR6##
a) Fourteen (14) g (0.04 mol) of N.sub.3 P.sub.3 Cl.sub.6 and 180 ml of THF
are introduced into a 250-ml double-jacketed reactor and maintained at
0.degree. C. After dissolution, 9.4 ml (0.067 mol) of triethylamine is
added and thereafter a solution comprising 3 g (0.0336 mol) of
4-aminobutanol and 40 ml of THF is added dropwise over a period of fifteen
minutes. The reaction mixture is agitated at 0.degree. C. for a period of
one hour and then at a temperature of 25.degree. C. for 24 hours. The
insoluble material is filtered off and the THF evaporated. The residue
contains mostly the desired product but accompanied by two by-products.
Chromatography of the mixture through a column of silica (60 g) and
elution of the column with 60% cyclohexane, 20% methylenechloride, and 20%
ethylacetate, followed by evaporation of the fractions containing the
product, gives a residue which is agitated with hexane. After filtration,
rinsing with hexane and drying at a temperature of about 40.degree. C.,
there is obtained 4.6 g of
2,2,4,4-tetrachloro-2,2,4,4-tetrahydro-7-oxa-1,3,5,12-tetraaza-2,4,6.lambd
a..sup.5 -triphosphaspiro-[5,6]-dodeca-1,3,5-triene.
Yield 38%; MP=133.degree. C.
b) The product of the preceding step (4.7 g; 0.0129 mol) is dissolved in 70
ml of THF. The resulting solution is introduced into a 150-ml
double-jacketed reactor. Triethylamine (10.8 ml; 0.0775 mol) is added to
the solution at a temperature of -10.degree. C. Then, over a period of
fifteen minutes, a solution comprising 5.3 ml (0.103 mol) of aziridine and
15 ml of THF is added dropwise. The reaction mixture is stirred at
0.degree. C. over a period of one hour and at 25.degree. C. for 24 hours.
The insoluble material is filtered off and the THF evaporated. The residue
is then dissolved in a minimum of chloroform and chromatographed by
passage through a silica column (45 g) using a mixture of 95% chloroform,
4.5% methanol, and 0.5% ammonia as eluant. The fractions containing the
desired product are evaporated and the residue is recrystallized from 30
ml of ethylacetate. After filtration, rinsing with ethylacetate, and
drying at a temperature of about 40.degree. C., two (2) g of Compound 9
are obtained.
Yield 40%; MP 129.degree. C.
EXAMPLE 4
Other Compounds of the Invention
Additional examples of related compounds produced in a manner analogous to
that given for the production of Compounds 1, 6, and 9 in the foregoing,
are as follows:
Compound 2
7,7,9,9-Tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,8,10-tetraaza-5.lam
bda..sup.5,7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene.
Compound 3
2,2,4,4-Tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,5,11-tetraaza-2,4,6
.lambda..sup.5 -triphosphaspiro-[5,5]-undeca-1,3,5-triene.
Compound 4
11-Cyclohexyl-2,2,4,4-tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,5,11-
tetraaza-2,4,6.lambda..sup.5 -triphosphaspiro-[5,5]-undeca-1,3,5-triene.
Compound 5
4-Phenylmethyl-7,7,9,9-tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,8,10
-tetraaza-5.lambda..sup.5,7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene.
Compound 7
4-(2-Phenylethyl)-7,7,9,9-tetra-1-aziridinyl-7,7,9,9-tetrahydro-1-oxa-4,6,8
,10-tetraaza-5.lambda..sup.5,7,9-triphosphaspiro-[4,5]-deca-5,7,9-triene.
Compound 8
11-(2-Phenylethyl)-2,2,4,4-tetra-1-aziridinyl-2,2,4,4-tetrahydro-7-oxa-1,3,
5,11-tetraaza-2,4,6.lambda..sup.5
-triphosphaspiro-[5,5]-undeca-1,3,5-triene.
The following Table summarizes the characteristics of the nine (9)
compounds produced according to the foregoing nine (9) examples.
__________________________________________________________________________
##STR7##
RMN .sup.31 P
No.
R (CH.sub.2).sub..eta.
Recryst. Solv.
Yield
Formula M.W.
MP .degree.C.
PAs.sub.2
P Spiro
J
__________________________________________________________________________
1 CH.sub.3
(CH.sub.2).sub.2
THF 56% C.sub.11 H.sub.23 N.sub.8 OP.sub.3
376.28
170 39.55
32.37
39.04
41.5
2 H (CH.sub.2).sub.2
ACOEt-EI*1-1
59% C.sub.10 H.sub.21 N.sub.8 OP.sub.3
362.25
112 39.68
36.33
43.3
39.78 37.3
3 H (CH.sub.2).sub.3
THF 67% C.sub.11 H.sub.23 N.sub.8 OP.sub.3
376.28
145 38.45
19.04
38.24
4 cyclohexyl
(CH.sub.2).sub.3
IE 47% C.sub.17 H.sub.33 N.sub.8 OP.sub.3
458.43
101 38.34
19.48
39.95
5 benzyl
(CH.sub.2).sub.2
ACOEt-EI 1-1
41% C.sub.17 H.sub.27 N.sub.8 OP.sub.3
452.38
144 39.7
31.67
40.2
6 benzyl
(CH.sub.2).sub.3
ACOEt-EI 1-1
50% C.sub.18 H.sub.29 N.sub.8 OP.sub.3
466.41
133 38.56
20.89
39.35
7 phenethyl
(CH.sub.2).sub.2
ACOEt-EI 1-1
60% C.sub.18 H.sub.29 N.sub.8 OP.sub.3
466.41
124 39.5
31.48
40.35
8 phenethyl
(CH.sub.2).sub.3
ACOEt-EI 1-1
35% C.sub.19 H.sub.31 N.sub.8 OP.sub.3
480.43
116 38.4
20.42
38.68
9 H (CH.sub.2).sub.4
ACOEt 40% C.sub.12 H.sub.25 N.sub.8 OP.sub.3
390.31
129
__________________________________________________________________________
*IE = isopropyl ether
EXPERIMENTS
Various pharmacological and toxicological tests were carried out on the
compounds which form the object of the present invention.
1. Pharmacological Activity
a) In Vitro cytotoxicity
The cytotoxic activity in vitro was evaluated by the determination of the
IC.sub.50 (concentration for which 50% inhibition of cell growth is
obtained) on mouse L1210 leukemic cells.
The IC.sub.50 is evaluated by means of a cell counter.
______________________________________
Compound IC.sub.50 (.mu.M)
______________________________________
1 9
2 8.7
3 2.3
4 9.9
5 5.8
6 5.8
7 7.8
8 6.5
______________________________________
b) In vivo
The antitumoral activity in vivo was evaluated on the P 388 model in the
mouse. This model corresponds to leukemic cells grafted i.p. on day D.
The drug is administered in repeated dosage on D1, D3, D5.
The index "T/C" corresponds to the survival (%) of the treated animals as
compared with the control animals.
The "T/C" of the products of the invention ranges from 130 to >300.
2. Toxicity
The compounds of the invention are of moderate toxicity in the doses
tested, in terms of the hematological parameters and the growth rate,
i.e., weight increases as a function of time.
3. Therapeutic Applications
In view of their pharmacological properties, the compounds of the present
invention can be used in animal including human therapy in the treatment
of cancer pathology.
The pharmaceutical preparations containing these active principles can be
formulated for administration orally, intravenously, or intraperitoneally.
It is also possible to combine them with other pharmaceutically-and
therapeutically-acceptable active principles.
REPRESENTATIVE PHARMACEUTICAL FORMULATION
For the preparation of an injectable pharmaceutical formulation, about 10
mg to about 200 mg of a compound according to the present invention is
dissolved in two (2) ml of an aqueous solution buffered at a pH of about
pH8 to about pH9, for example by the employment of a mixture of Na.sub.2
HPO.sub.4.7H.sub.2 O and NaH.sub.2 PO.sub.4.H.sub.2 O, the solution then
being rendered isotonic by the addition of sodium chloride, generally in
accord with conventional knowledge of the art.
Other pharmaceutical compositions or formulations of the active compounds
of the invention may also be employed, and the foregoing is merely
representative. All of the usual diluents, carriers, or adjuvants which
are conventional in the art may be employed to facilitate administration
of the compounds of the present invention, which obviously may be
administered in combination with other active ingredients according to
standard practice of the art. In any event, a pharmaceutical composition
of the invention will contain an effective cytotoxic or antineoplastic
amount of a compound of the invention in combination with a
pharmaceutically-acceptable diluent or carrier. As indicated in the
foregoing, the pharmaceutical composition may contain between about 10 and
about 200 mg of active ingredient per unit dosage form.
The method of treatment according to the invention consists essentially of
the step of administering to a living animal, including a human, suffering
from a neoplastic disease or condition which is responsive to treatment
with a compound of the invention and susceptible thereto, an effective
antineoplastic amount of a compound of the present invention, preferably
in the form of a pharmaceutical composition thereof in which it is present
together with a pharmaceutically-acceptable carrier or diluent.
It will of course be apparent to one skilled in the art that the amount of
the active ingredient must be an effective cytotoxic or antineoplastic
amount and also that the neoplastic disease or condition treated must be
one which is susceptible to treatment with a compound of the invention,
that is, one which is responsive to treatment therewith. It will further
be apparent at one skilled in the art that the exact form of the
pharmaceutically-acceptable diluent, carrier, or adjuvant employed, as
well as the particular pharmaceutical form employed, whether tablet,
capsule, suppository, or injectible solution, will be dependent upon the
exact condition involved, as well as the condition of the patient
involved, and as usual in accord with the preferences and directions of
the physician or veterinarian in charge.
It is therefore seen from the foregoing that new compounds, pharmaceutical
compositions thereof, a method of treating and ameliorating susceptible
neoplastic diseases or conditions with such a compound or pharmaceutical
composition of the invention, and a method of making the same, have all
been provided, and that all of the objects of the invention have thus been
fulfilled.
It is to be understood that the invention is not to be limited to the exact
details of operation of exact compounds, compositions, methods, or
procedures shown and described, as obvious modifications and equivalents
will be apparent to one skilled in the art.
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